Long-term treatment with UDCA (13-15 mg/kg/day) in patients with PBC improves biochemical liver tests, delays histological progression, and prolongs survival without liver transplantation . UDCA monotherapy appears sufficient for many patients as suggested by long-term observational data . However, the transplant-free survival rate of UDCA-treated patients remains significantly lower than that of an age-matched and sex-matched control population. Therefore, there is a continued need for new therapeutic options in PBC. In this article we review and discuss the following issues : the appropriate selection of patients requiring new therapeutic options, the role of budesonide in the management of these patients, the emerging place of PPAR alpha ligands as antiinflammatory and immunomodulating agents in PBC.

Introduction

Ursodeoxycholic acid (UDCA) is currently the only drug approved specifically for the treatment of primary biliary cirrhosis (PBC). Long-term treatment with UDCA (13-15 mg/kg/day) in patients with PBC improves biochemical liver tests, delays histological progression, and prolongs survival without liver transplantation (LT). UDCA monotherapy appears sufficient for many patients as suggested by long-term observational data (1-3). However, the transplant-free survival rate of UDCA-treated patients remains significantly lower than that of an age-matched and sex-matched control population(3). Therefore, there is a continued need for new therapeutic options in PBC.

Identification of the patients requiring new therapeutic options

We have previously shown that serum bilirubin, histological stage, and lymphocytic interface hepatitis were the main predictive factors of UDCA treatment failure in patients with PBC(4,5) However, these prognostic indices have some limitations: (1) hyperbilirubinemia concerns a minority of treated patients; and (2) histological examination of the liver implies an invasive procedure, that is, biopsy, that precludes its repeated use. Biochemical response to UDCA, especially changes in the serum activities of alkaline phosphatase (ALP) and aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), may appear as a more sensitive and applicable indicator of treatment efficacy. In this regard, a study in Barcelona showed that a decrease of more than 40% in the serum activity of ALP, or normal levels of ALP, after 1 year of UDCA treatment was associated with excellent long-term survival in patients with PBC, which was similar to that estimated for a standardized controlpopulation(1) By contrast, the survival rate of patients without such criteria of response to UDCA was significantly altered. The prognostic impact of the‘‘Barcelona criteria” was confirmed in a large independent cohort of PBC patients for which a serum bilirubin<1 mg/dL (17 micromol/L), ALP<3 ULN, and AST <2ULN (‘‘Paris criteria”) after one year of treatment evenbetter identified those with a good long-term prognosisof a 90% (vs. 51%) ten year transplant-free survival [2].The above studies indicated that there is no full agreement on the definition of the biochemical response as a surrogate marker of survival without transplantation. A probable explanation may lie in the variation in the patient populations studied including patients with either early or late stages. Accordingly, we sought to refine our definition of biochemical response by using more extended end-points and stringent criteria (histological progression to cirrhosis, complications of cirrhosis, liver transplantation or liver-related death) in an homogeneous cohort of patients with early stage disease. The efficiency of several combinations of serum bilirubin, ALP, and AST threshold values to predict outcome was assessed after 1 year of treatment in 165 patients with ealy stage PBC. The most accurate discrimination of the patients according to the multiple endpoints was given by the following definition: serum total bilirubin ≤ 1.0 mg/dl, and ALP ≤ 1.5x ULN, and AST ≤ 1.5x ULN. According to this definition, responders (n=79, 48%) and non-responders (n=86, 52%) were equally distributed, but all the events were observed among non-responders (p< 0.0001). Accordingly its sensitivity was 100% and specificity 51% for the prediction of development of cirrhosis and liver failure.

UDCA and budesonide for patients with features of severe PBC with suboptimal response to UDCA alone

The use of corticosteroids to suppress the inflammation in PBC has been always considered as a very attractive approach (6-9), but at the cost of serious side effects especially aggravating osteopenia. Budesonide, a non halogenated glucocorticoid with a high first-pass hepatic metabolism and a high affinity for the glucocorticoid receptor exerts fewer side effects than conventional corticosteroids in patients with inflammatory bowel disease [10 ] or autoimmune hepatitis [11 ]. In non-selected PBC patients with early stage disease, oral budesonide (6-9 mg/d) combined with standard dose of UDCA has been shown to be superior to UDCA alone in terms of both biochemistries and histology in two short-term controlled studies [12-3 ]. However, in a pilot study involving patients with advanced stage disease with a suboptimal response to UDCA, budesonide (9 mg/d for one year) was associated with a worsening of the Mayo risk score and bone loss [14 ]. We assessed the possible therapeutic benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) as both an immunosuppressive and steroid-sparing agent in non-cirrhotic PBC patients at high risk of developping cirrhosis or liver failure (15).

Patients with a suboptimal response to UDCA at the daily dose of 13 to 15 mg/kg after at least 12 months of therapy, defined by the persistent elevation of alkaline phosphatases above 250 U/l (N<110 U/l) or AST > 70 U/l (N<35 U/l) or total serum bilirubin > 17micromol/L with conjugated bilirubin >7micromol/L, and presence of moderate or severe lymphocytic interface hepatitis at liver biopsy. Inegibility criteria were the presence of compensated or decompensated cirrhosis, hyperbilirubinemia (>51 micromol/L), autoimmune hepatitis defined by at least 2 of the following criteria, ALT > 200 U/l (< 35 U/l), IgG > 25 g/l and severe lymphocytic interface hepatitis, contraindication or refusal to receive glucocorticoids. The treatment regimen included budesonide (6 mg/d) and MMF (1.5 g/d), always in combination with UDCA (13-15 mg/kg/d). All the patients received calcium (1 g/d) and vitamin D (800 UI/d) and biphosphonates. Rifampicin (300-600mg/d) was given to patients with disturbing pruritus if necessary. The follow-up included clinical and biochemical evaluation every three to six months. Liver biopsy was performed after 3 years of therapy in all the patients.

Baseline demographic and clinical features of the patients enrolled in the study are shown in Table 1:

Table 1. Clinical characteristics of the patients at enrollment (n=15).

Six out of the 15 patients (41%) experienced a complete normalization of biochemistries under therapy, and 7 (47%) showed a partial biochemical response as defined by a serum bilirubin < 1 mg/dl, AST < 70 IU/l (i.e, < two fold the upper limit of normal) and ALP< 250 IU/l (i.e, < two fold the upper limit of normal).

Histological activity and fibrosis were markedly improved (Table 2).

Table 3. Histological activity and fibrosis grades in the initial (at enrollment) and the final liver biopsy.

Initial

Final

p

Activity

A0-A1

0 (0%)

12 (80%)

.02

A2

12 (80%)

3(20%)

A3

3 (20%)

0(10%)

Fibrosis

F0-F1

3 (20%)

9 (60%)

.02

F2

8 (53%)

4 (27%)

F3

4 (27%)

2 (13%)

F4

0 (0%)

0(0%)

P values as given by the Fisher’s exact test. Activity and fibrosis scoring according to METAVIR.

The combined therapy was well tolerated in our patients.

This open study confirms that UDCA combined with budesonide is highly effective in non cirrhotic patients and strongly suggests that the combination of UDCA with budesonide and MMF is able to slowdown the course of PBC in patients not responding to UDCA alone. Further studies using budesonide and involving selected patients with suboptimal response to UDCA and severe liver inflammation are warranted to support the present observational study.

Fibrates and UDCA for PBC patients with a suboptimal response to UDCA alone.

Fibrates derivatives have a 40-year history in the management of dys- lipidemia. Their use led to the discovery of peroxisome proliferator-activated receptor (PPAR) genes. This class of drugs is generally well-tolerated; however, safety issues have arisen from their use. Their

parsimonious use in Europe for the treatment of PBC came initially from reports who showed that cloﬁbrate could induce paradoxical hypercholesterolemia, intra-hepatic, and choledocolithiasis in patients with PBC(16-7). In addition to the suspected possible role of clofibrate in human liver carcinogenesis, which was demonstrated in rodents, discouraged hepatologists from prescribing ﬁbrates even in the case of dyslipidemia in their patients with PBC.

Fenofibrate and bezafibrate are members of fibrate class agents and works as ligands of PPARα, showing a potent triglyceride-lowering effect. The lowering effect of fibrates on ALP levels in dyslipidemic patients and the notion that fibrate-induced biliary phospholipid secretion could protect the biliary epithelium in PBC led to the use of fibrates mainly in Japan. The rationale for the use of fibrates is now reinforced since their antiinflammatory properties are well established. Indeed, PPAR ligands have anti-inflammatory activity in a variety of mouse models of acute and chronic inflammation. In chronic inflammation, ligand-bound PPAR alpha represses production of IFNg and IL-17 by CD4+ T cells. PPAR ligands also repress expression of cell adhesion molecules on endothelial cells and the secretion of chemokines by epithelial and other cells, decreasing the recruitment of leukocytes to the site of inflammation. The anti-inflammatory activity of PPAR ligands in mouse models suggests their possible use for treating human inflammatory and autoimmune diseases (18-9).

Up to now, reports including more than 300 PBC patients have shown that bezafibrate or fenofibrate improve liver biochemistries in PBC. In two small controlled trials, Iwasaki and colleagues (20) showed that bezaﬁbrate (400 mg/day) was as effective as UDCA (600 mg/day) in reducing liver enzymes. They showed that the combination of bezaﬁbrate and UDCA produces a higher reduction in ALP levels than does UDCA (600 mg/day) alone, but there were no signiﬁcant differences in other biochemistries between the two therapeutic regimens. We explored the effects of fenofibrate (200mg/day) for two years in non cirrhotic PBC patients not acheiving normalization of their liver biochemistries under UDCA therapy. We found that the combination of fenofibrate and UDCA produced a sustained improvement of ALP and ALT in the majority of the 29 patients included in the open trial. Morever immune parameters (IgM and IgG levels) were significantly improved . There was also a significant trend in the improvement of serum bile acids levels as well as in liver transient elastometric data suggesting a real effect on the liver inflammatory process. All the available data therefore suggest that fibrates emerge as a new therapeutic option in the treament of PBC. As for UDCA over the last 20 years, it remains to be demonstrated that the effects of ﬁbrates will not only be “cosmetic” but really effective in terms of progression toward end-stage disease. Lessons from the UDCA story will certainly be useful to achieve this goal.